TY - JOUR T1 - THE EFFECT OF DIAZEPAM ON THE METABOLISM OF METHADONE BY THE LIVER OF METHADONE-DEPENDENT RATS JF - Drug Metabolism and Disposition JO - Drug Metab Dispos SP - 458 LP - 463 VL - 2 IS - 5 AU - THEODORE C. SPAULDING AU - LINDA MINIUM AU - ALVIN N. KOTAKE AU - A. E. TAKEMORI Y1 - 1974/09/01 UR - http://dmd.aspetjournals.org/content/2/5/458.abstract N2 - The N-demethylation of methadone by 9000g supernatant fractions of hepatic homogenates was investigated in methadone-dependent rats. In these studies rats were administered methadone hydrochloride by allowing free access to the drug dissolved in the drinking water (0.5 mg/ml). Rats in the control group ingested tap water. The Vmax of N-demethylation by liver supernatant fractions from methadone-dependent rats was 40-50% higher than that from control animals, whereas the Km values did not differ significantly. The increase in Vmax after chronic administration of methadone was not reflected by alteration of either the amount of cytochrome P-450 or the ethyl isocyanide binding. Diazepam was found to be a competitive inhibitor of N-demethylation of methadone with a Ki of 1.7 x 10-4 M when incubated with hepatic supernatant fractions from control rats. However, diazepam was an uncompetitive inhibitor when incubated with supernatant fractions from livers of methadone-dependent rats. These data indicate that, unlike other opioid narcotics, methadone increased its own metabolism upon chronic treatment. Further, diazepam was shown to be a fairly effective inhibitor of the N-demethylation of methadone which may explain in part the enhanced effect of methadone observed in narcotic addicts when the combination is taken. Copyright © 1974 by The American Society for Pharmacology and Experimental Therapeutics ER -